DESCRIPTION (Applicant's Abstract): Naltrexone, an opioid antagonist, is currently used in oral tablet form to help maintain opioid addicts in a drug-free state. Most recently, naltrexone has been indicated as an adjunct in the treatment of alcohol dependence, with some reports that alcohol craving was actually reduced in certain alcoholic populations. Transdermal delivery of naltrexone is desirable for opioid addicts and alcoholics in order to help reduce side effects associated with oral therapy and improve compliance. Previous reports say that naltrexone itself does not have the essential physicochemical properties that would allow a therapeutic dose of the drug to cross the human skin barrier. We plan to design and synthesize naltrexone prodrugs with increased skin permeability to make a therapeutically successful drug delivery system. We hypothesize that 3-alkyl-ester prodrugs of naltrexone will improve the transdermal delivery rate of naltrexone, and that these prodrugs will make excellent research tools to produce quantitative structure-activity relationships (QSARs) for transdermal flux and concurrent metabolism. These prodrugs should improve naltrexone delivery rates across the skin, because they are more lipophilic, less crystalline and therefore more soluble than naltrexone. The specific objectives of this project include: (1) to synthesize a series of naltrexone 3-alkyl-ester prodrugs to elucidate fundamental QSARs for transdermal flux and concurrent esterase metabolism of the prodrug, (2) to characterize the physicochemical parameters of naltrexone and its 3-alkyl-ester prodrugs to be used in QSAR analysis including molecular weight, molecular volume, lipophilicity, hydrogen-bonding potentials, melting points, heats of fusion, and solubilities in select solvents, (3) to measure the naltrexone 3-alkyl-ester prodrugs' penetration and concurrent metabolism through human skin in vitro, (4) and to develop QSARs for transdermal flux and concurrent metabolism using multiple regression analysis of equations including calculated physicochemical parameters, experimental physicochemical parameters and in vitro human skin diffusion parameters. These objectives should help us not only identify the critical parameters involved in optimization of transdermal prodrug use, but also quantify how important these parameters are in determining the prodrug flux and concurrent metabolism.